Sensitive quantification of free pazopanib using ultra-high performance liquid chromatography coupled to tandem mass spectrometry and assessment of clinical application
Sensitive quantification of free pazopanib using ultra-high performance liquid chromatography coupled to tandem mass spectrometry and assessment of clinical application
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DOI：
10.1016/j.jpba.2021.114348
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发表时间：
2021-09-09
影响因子：
3.4
通讯作者：
Itoh, Hiroki
中科院分区：
文献类型：
--
作者：
Matsumoto, Asami;Shiraiwa, Ken;Itoh, Hiroki
帕唑帕尼在日本广泛用于治疗肾细胞癌和软组织肿瘤。尽管一些报告证明了帕唑帕尼治疗药物监测 (TDM) 的有用性，但这些研究仅测量了帕唑帕尼总浓度。对于帕唑帕尼等具有高蛋白结合率的药物，测量游离浓度在临床上可能比测量总浓度更有用。在本研究中，我们旨在开发一种使用超高效液相色谱串联质谱 (UHPLC-MS/MS) 定量人血浆中游离帕唑帕尼的高通量方法。通过超滤分离游离帕唑帕尼。使用 96 孔板进行简单的固相萃取步骤后，通过 UHPLC-MS/MS 在正电喷雾电离模式下对帕唑帕尼进行分析。该新方法满足美国食品药品监督管理局测定验证指南的要求，定量下限为0.05 ng/mL。校准曲线在 0.05-50 ng/mL 的浓度范围内呈线性。平均恢复率为 66.9 +/- 2.1%（平均值 +/- SD）。所有质量控制水平的精密度均低于 7.02%，准确度均在 10.60% 以内。基质效应在 44.4% 和 60.4% 之间变化。该测定成功地应用于测量三名接受帕唑帕尼治疗软组织肿瘤的患者的游离帕唑帕尼浓度。我们成功开发了一种新型高通量 UHPLC-MS/MS 方法，用于定量人血浆中游离帕唑帕尼。该方法可应用于临床环境中接受帕唑帕尼治疗的患者的 TDM。 (c) 2021 Elsevier B.V. 保留所有权利。
Pazopanib is widely used to treat renal cell carcinomas and soft tissue tumors in Japan. Although several reports demonstrated the usefulness of therapeutic drug monitoring (TDM) of pazopanib, those studies measured only total pazopanib concentration. For drugs with high protein binding rates such as pazopanib, measuring free concentrations may be clinically more useful than measuring total concentrations. In this study, we aimed to develop a high-throughput method for quantification of free pazopanib in human plasma using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). Free pazopanib was separated by ultrafiltration. After a simple solid-phase extraction step using a 96-well plate, pazopanib was analyzed by UHPLC-MS/MS in positive electrospray ionization mode. The novel method fulfilled the requirements of the US Food and Drug Administration guidelines for assay validation, and the lower limit of quantification was 0.05 ng/mL. The calibration curve was linear over the concentration range of 0.05-50 ng/mL. The average recovery rate was 66.9 +/- 2.1% (mean +/- SD). The precision was below 7.02%, and accuracy was within 10.60% across all quality control levels. Matrix effect varied between 44.4% and 60.4%. This assay was successfully applied to measure trough free pazopanib concentrations in three patients treated with pazopanib for soft tissue tumors. We succeeded to develop a novel high-throughput UHPLC-MS/MS method for quantification of free pazopanib in human plasma. This method can be applied to TDM for patients receiving pazopanib in the clinical setting. (c) 2021 Elsevier B.V. All rights reserved.